Mixed effects smoothing spline analysis of variance

We propose a general family of nonparametric mixed effects models. Smoothing splines are used to model the fixed effects and are estimated by maximizing the penalized likelihood function. The random effects are generic and are modelled parametrically by assuming that the covariance function depends on a parsimonious set of parameters. These parameters and the smoothing parameter are estimated simultaneously by the generalized maximum likelihood method. We derive a connection between a nonparametric mixed effects model and a linear mixed effects model. This connection suggests a way of fitting a nonparametric mixed effects model by using existing programs. The classical two-way mixed models and growth curve models are used as examples to demonstrate how to use smoothing spline analysis-of-variance decompositions to build nonparametric mixed effects models. Similarly to the classical analysis of variance, components of these nonparametric mixed effects models can be interpreted as main effects and interactions. The penalized likelihood estimates of the fixed effects in a two-way mixed model are extensions of James–Stein shrinkage estimates to correlated observations. In an example three nested nonparametric mixed effects models are fitted to a longitudinal data set.     

A revisit to two-way factorial ANOVA with mixed effects and interactions

Abstract

Two mixed models exist in analysis of two-way factorial ANOVA with mixed effects and interactions: the constrained and unconstrained models. The constrained model is unfavored because there is no convincing rationale for the enforced constraints on its random interactions and a lack of clear interpretation about its variance components. The purpose of this study is to further explore the relationship between these two models. We reveal some nice features of the constrained model on partition of the responsive variance. An alternative formulation of ANOVA that follows from this exploration is also presented.     

Harmonic mean approach to unbalanced mixed effects models under heteroscedastic variances

In this paper we consider unbalanced mixed models (Scheffe's model) under heteroscedastic variances. By using the harmonic mean approach, It is shown that the problems appear to be anologous to those problems from balanced mixed models under homoscedastic variance. Thus, by using harmonic mean approach, statistical inferences about fixed effects and variance components are derived by using those from balanced models under homoscedastic variance. Laguerre polynomial expansion is used Lo approximate sampling distributions of relevant statistics.     

A unified approach to rank tests for mixed models

The nonparametric version of the classical mixed model is considered and the common hypotheses of (parametric) main effects and interactions are reformulated in a nonparametric setup. To test these nonparametric hypotheses, the asymptotic distributions of quadratic forms of rank statistics are derived in a general framework which enables the derivation of the statistics for the nonparametric hypotheses of the fixed treatment effects and interactions in an arbitrary mixed model. The procedures given here are not restricted to semiparametric models or models with additive effects. Moreover, they are robust to outliers since only the ranks of the observations are needed. They are also applicable to pure ordinal data and since no continuity of the distribution functions is assumed, they can also be applied to data with ties. Some approximations for small sample sizes are suggested and analyzed in a simulation study. The application of the statistics and the interpretation of the results is demonstrated in several worked-out examples where some data sets given in the literature are re-analyzed.     

Analysis of overdispersed paired count data

This article is about the statistical analysis of overdispersed paired count data for comparing two treatments. The data consist of the number of events obtained in a stratum during the fixed observation period. Three types of model are discussed: the Poisson, a mixed, and a semiparametric model. Overdispersion is represented in the last two models but not in the Poisson model. Of particular interests are to examine whether there is any loss of efficiency in using the estimate of the treatment effect obtained under other two models if the mixed model is true, and also whether overdispersion leads to a larger variance of the estimate than that expected from the Poisson model. It is shown that all three models provide the same estimate of the treatment effect (i.e., there is no loss of efficiency) and that the variance of the estimate of the treatment effect obtained under the Poisson model is the same as that based on the mixed model. However, the semiparametric model provides the variance of the estimate larger than those obtained under the other two models.     

Tests of additivity in mixed and fixed effect two-way ANOVA models with single sub-class numbers

In variety testing as well as in psychological assessment, the situation occurs that in a two-way ANOVA-type model with only one replication per cell, analysis is done under the assumption of no interaction between the two factors. Tests for this situation are known only for fixed factors and normally distributed outcomes. In the following we will present five additivity tests and apply them to fixed and mixed models and to quantitative as well as to Bernoulli distributed data. We consider their performance via simulation studies with respect to the type-I-risk and power. Furthermore, two new approaches will be presented, one being a modification of Tukey’s test and the other being a new experimental design to test for interactions.     

Optimal cross-over designs for nonlinear mixed models using a first-order expansion

We consider the construction of optimal cross-over designs for nonlinear mixed effect models based on the first-order expansion. We show that for AB/BA designs a balanced subject allocation is optimal when the parameters depend on treatments only. For multiple period, multiple sequence designs, uniform designs are optimal among dual balanced designs under the same conditions. As a by-product, the same results hold for multivariate linear mixed models with variances depending on treatments.     

Predicting random effects with an expanded finite population mixed model

Prediction of random effects is an important problem with expanding applications. In the simplest context, the problem corresponds to prediction of the latent value (the mean) of a realized cluster selected via two-stage sampling. Recently, Stanek and Singer [Predicting random effects from finite population clustered samples with response error. J. Amer. Statist. Assoc. 99, 119–130] developed best linear unbiased predictors (BLUP) under a finite population mixed model that outperform BLUPs from mixed models and superpopulation models. Their setup, however, does not allow for unequally sized clusters. To overcome this drawback, we consider an expanded finite population mixed model based on a larger set of random variables that span a higher dimensional space than those typically applied to such problems. We show that BLUPs for linear combinations of the realized cluster means derived under such a model have considerably smaller mean squared error (MSE) than those obtained from mixed models, superpopulation models, and finite population mixed models. We motivate our general approach by an example developed for two-stage cluster sampling and show that it faithfully captures the stochastic aspects of sampling in the problem. We also consider simulation studies to illustrate the increased accuracy of the BLUP obtained under the expanded finite population mixed model.     

Robust linear mixed models with skew-normal independent distributions from a Bayesian perspective

Linear mixed models were developed to handle clustered data and have been a topic of increasing interest in statistics for the past 50 years. Generally, the normality (or symmetry) of the random effects is a common assumption in linear mixed models but it may, sometimes, be unrealistic, obscuring important features of among-subjects variation. In this article, we utilize skew-normal/independent distributions as a tool for robust modeling of linear mixed models under a Bayesian paradigm. The skew-normal/independent distributions is an attractive class of asymmetric heavy-tailed distributions that includes the skew-normal distribution, skew-t, skew-slash and the skew-contaminated normal distributions as special cases, providing an appealing robust alternative to the routine use of symmetric distributions in this type of models. The methods developed are illustrated using a real data set from Framingham cholesterol study.     

Estimation using penalized quasilikelihood and quasi-pseudo-likelihood in Poisson mixed models

We consider two estimation schemes based on penalized quasilikelihood and quasi-pseudo-likelihood in Poisson mixed models. The asymptotic bias in regression coefficients and variance components estimated by penalized quasilikelihood (PQL) is studied for small values of the variance components. We show the PQL estimators of both regression coefficients and variance components in Poisson mixed models have a smaller order of bias compared to those for binomial data. Unbiased estimating equations based on quasi-pseudo-likelihood are proposed and are shown to yield consistent estimators under some regularity conditions. The finite sample performance of these two methods is compared through a simulation study.     

Limiting admissible estimators for variance components

Simultaneous estimation of the vector of the variance components for mixed and random models under the quadratic loss function is considered. For a large class of such models there are identified classes of admissible biased invariant quadratic estimators that are better than some admissible unbiased estimators. Numerous numerical results presented in the paper show that for many of the commonly used balanced models the improvements in the quadratic risk may be considerable over a large set of the parameter space.     

An Alternative Estimation Approach for the Heterogeneity Linear Mixed Model

In this article, an alternative estimation approach is proposed to fit linear mixed effects models where the random effects follow a finite mixture of normal distributions. This heterogeneity linear mixed model is an interesting tool since it relaxes the classical normality assumption and is also perfectly suitable for classification purposes, based on longitudinal profiles. Instead of fitting directly the heterogeneity linear mixed model, we propose to fit an equivalent mixture of linear mixed models under some restrictions which is computationally simpler. Unlike the former model, the latter can be maximized analytically using an EM-algorithm and the obtained parameter estimates can be easily used to compute the parameter estimates of interest.     

Restricted likelihood ratio lack-of-fit tests using mixed spline models

Summary.  Penalized regression spline models afford a simple mixed model representation in which variance components control the degree of non-linearity in the smooth function estimates. This motivates the study of lack-of-fit tests based on the restricted maximum likelihood ratio statistic which tests whether variance components are 0 against the alternative of taking on positive values. For this one-sided testing problem a further complication is that the variance component belongs to the boundary of the parameter space under the null hypothesis. Conditions are obtained on the design of the regression spline models under which asymptotic distribution theory applies, and finite sample approximations to the asymptotic distribution are provided. Test statistics are studied for simple as well as multiple-regression models.     

Applying functional data analysis to assess tele-interpersonal psychotherapy's efficacy to reduce depression

The use of parametric linear mixed models and generalized linear mixed models to analyze longitudinal data collected during randomized control trials (RCT) is conventional. The application of these methods, however, is restricted due to various assumptions required by these models. When the number of observations per subject is sufficiently large, and individual trajectories are noisy, functional data analysis (FDA) methods serve as an alternative to parametric longitudinal data analysis techniques. However, the use of FDA in RCTs is rare. In this paper, the effectiveness of FDA and linear mixed models (LMMs) was compared by analyzing data from rural persons living with HIV and comorbid depression enrolled in a depression treatment randomized clinical trial. Interactive voice response systems were used for weekly administrations of the 10-item Self-Administered Depression Scale (SADS) over 41 weeks. Functional principal component analysis and functional regression analysis methods detected a statistically significant difference in SADS between telphone-administered interpersonal psychotherapy (tele-IPT) and controls but linear mixed effects model results did not. Additional simulation studies were conducted to compare FDA and LMMs under a different nonlinear trajectory assumption. In this clinical trial with sufficient per subject measured outcomes and individual trajectories that are noisy and nonlinear, we found FDA methods to be a better alternative to LMMs.     

Generalized additive mixed models

Following the extension from linear mixed models to additive mixed models, extension from generalized linear mixed models to generalized additive mixed models is made, Algorithms are developed to compute the MLE's of the nonlinear effects and the covariance structures based on the penalized marginal likelihood. Convergence of the algorithms and selection of the smooth param¬eters are discussed.     

Analyzing Binomial Data in a Split-Plot Design: Classical Approach or Modern Techniques?

Modeling data that are non-normally distributed with random effects is the major challenge in analyzing binomial data in split-plot designs. Seven methods for analyzing such data using mixed, generalized linear, or generalized linear mixed models are compared for the size and power of the tests. This study shows that analyzing random effects properly is more important than adjusting the analysis for non-normality. Methods based on mixed and generalized linear mixed models hold Type I error rates better than generalized linear models. Mixed model methods tend to have higher power than generalized linear mixed models when the sample size is small.     

Linear latent structure analysis: Mixture distribution models with linear constraints

A new method for analyzing high-dimensional categorical data, Linear Latent Structure (LLS) analysis, is presented. LLS models belong to the family of latent structure models, which are mixture distribution models constrained to satisfy the local independence assumption. LLS analysis explicitly considers a family of mixed distributions as a linear space, and LLS models are obtained by imposing linear constraints on the mixing distribution.LLS models are identifiable under modest conditions and are consistently estimable. A remarkable feature of LLS analysis is the existence of a high-performance numerical algorithm, which reduces parameter estimation to a sequence of linear algebra problems. Simulation experiments with a prototype of the algorithm demonstrated a good quality of restoration of model parameters.     

A Distribution-free Approach in Statistical Modelling with Repeated Measurements and Missing Values

Mixed effect models, which contain both fixed effects and random effects, are frequently used in dealing with correlated data arising from repeated measurements (made on the same statistical units). In mixed effect models, the distributions of the random effects need to be specified and they are often assumed to be normal. The analysis of correlated data from repeated measurements can also be done with GEE by assuming any type of correlation as initial input. Both mixed effect models and GEE are approaches requiring distribution specifications (likelihood, score function). In this article, we consider a distribution-free least square approach under a general setting with missing value allowed. This approach does not require the specifications of the distributions and initial correlation input. Consistency and asymptotic normality of the estimation are discussed.     

Multiplicative-interaction logit models for i×j×2 three-way tables

Multiplicative-interaction (M-I) logit models are proposed for three-way IxJx2 contingency tables where the third variable constitutes a binary response. Models are derived by assigning unknown scores to the categories and forming product interactions from them. Asymptotic results under special sampling constraints are derived for maximum likelihood estimates and the goodness-of-fit statistics. The class of models proposed in this paper are found to be useful when no obvious scores are available. An example is included.     

Design optimisation for pharmacokinetic modeling of a cocktail of phenotyping drugs

Our paper proposes a methodological strategy to select optimal sampling designs for phenotyping studies including a cocktail of drugs. A cocktail approach is of high interest to determine the simultaneous activity of enzymes responsible for drug metabolism and pharmacokinetics, therefore useful in anticipating drug–drug interactions and in personalized medicine. Phenotyping indexes, which are area under the concentration‐time curves, can be derived from a few samples using nonlinear mixed effect models and maximum a posteriori estimation. Because of clinical constraints in phenotyping studies, the number of samples that can be collected in individuals is limited and the sampling times must be as flexible as possible. Therefore to optimize joint design for several drugs (i.e., to determine a compromise between informative times that best characterize each drug's kinetics), we proposed to use a compound optimality criterion based on the expected population Fisher information matrix in nonlinear mixed effect models. This criterion allows weighting different models, which might be useful to take into account the importance accorded to each target in a phenotyping test. We also computed windows around the optimal times based on recursive random sampling and Monte‐Carlo simulation while maintaining a reasonable level of efficiency for parameter estimation. We illustrated this strategy for two drugs often included in phenotyping cocktails, midazolam (probe for CYP3A) and digoxin (P‐glycoprotein), based on the data of a previous study, and were able to find a sparse and flexible design. The obtained design was evaluated by clinical trial simulations and shown to be efficient for the estimation of population and individual parameters. Copyright © 2015 John Wiley & Sons, Ltd.